Frequency Therapeutics — Hearing Loss Regeneration

Here are 2 adjacent tones at 8000Hz with a 15 dB difference (one subject was tested with that difference from baseline).

Be sure to turn system volume down before playing since the 2nd tone is much louder.

My informed albeit unscientific opinion is that gaining 10-15 dB of hearing sensitivity in the frequencies of one's tinnitus will be a game changer.

 

https://jlaudio.zendesk.com/hc/en-us/articles/217201737-Doubling-Power-vs-Doubling-Output

“A change of 3 dB is accepted as the smallest difference in level that is easily heard by most listeners listening to speech or music. It is a slight increase or decrease in volume.”

Yeah perhaps he was misquoted, misspoke or he was trying to come at it from a different angle like this to make it sound more substantial in a way (not to say it wouldn’t be substantial to say doubled).

 

He probably wasn’t misquoted since he said tripled twice in the set of quotes from the article.

 

Right, it seems unnecessary. Double is pretty substantial.

 

FX-322 is injected into the middle ear, it enters the inner ear „liquid“ through the round window membrane.

What is the reason that the whole inner ear perilymph isn‘t mixed with FX-322?

Is the perilymph kind of viscous or will the liquid not move or circulate in a way?

 

The perilymph's current is actually stimulated from the tip of the apex (helicotrema) to the base.

"The mechanical vibrations of the stapes footplate at the oval window creates pressure waves in the perilymph of the scala vestibuli of the cochlea. These waves move around the tip of the cochlea through the helicotrema into the scala tympani and dissipate as they hit the round window."

This isn't the route of IT drugs traveling from the round window through the ear but is where drugs end up and are eliminated (but is useful for sampling drug concentrations just as sampling urine can tell you how much drug went through a kidney).

 

I found this which I think explains Frequency Therapeutics' multiple dosing rationale rather than increasing concentration:

"Bird and colleagues noted a large inter-variability in perilymph concentrations between patients after intratympanic administration of a methylprednisolone or a dexamethasone solution, providing a rationale for the reported variable clinical successes. Several factors can positively influence the clinical outcome. More than the absolute dose given at each administration or the total cumulative dose, the number of injections and the interval between them emerge as better predictors of a positive clinical outcome."

From: https://www.frontiersin.org/articles/10.3389/fncel.2019.00238/full

It also explains the variability if IT Dexamethasone. My guess based on this is that the patients who received 4 injections will have a much more pronounced result than the others.

Polarity is also a factor and it seems that some formulations of Dexamethasone are better than others but it seems lile frequency of dosing may actually be the biggest factor (but not the only one).

 

Some things that you should look at from this trial:

- Half of the patients got placebo and half FX-322

- Out of the half who got the drug half got the high dose and half got the low dose. Data suggests that the participants getting the high dose did gain improvements (hence Frequency Therapeutics has chosen to use the big dose in future trials)

- Those taking the big dose all had improvement of some kind. It is just the case that there were some who had an improvement which was not deemed statistically significant (hence how one subject had a 71% word score improvement but this was not deemed statistically significant) and some did not have a dB improvement.

- This was a safety dose trial only. Hence the trial results were a secondary and also extra measure Frequency Therapeutics added to this trial.

 

It looks like all but one of the moderate group kept most of their word score improvements, though it looks like for some they had to "scale up" a 25 word test because the one year retesting was done at different centers than the original testing (I wonder how much this is a factor). One person did decline and I wonder if there was something that happened within the year to instigate this.

It also looks like of the 4 who had the 10 dB improvements, after 1-2 years, 2 remained the same, someone gained an additional 5 dB and someone declined.

I really want to know more about the person who declined because they saw improvements initially and I wonder if they were less careful after or had some other incident in the year or an immune state that made them more prone to injury.

Phase 2a should be useful in sussing things like this out because the sample size is so much larger.

But it looks like most of the moderate hearing loss people kept most of their improvements. I wonder if repeat dosing (and also repeat courses every few years) may be needed in some people which presumably would be doable since the support cells are not depleted.

 

This is why I think that the comments he made in this article are somewhat loaded and also biased. When you go through the claims he has made, many of them do not even comply with the scientific facts or scientific standards. Furthermore I thought that nearly every comment this doctor made on Frequency Therapeutics and FX-322 was negative, appeared to be critical and also actually ignored the scientific facts and outcomes as well.

You've already referred to the dB improvement statement, which was one example.

However you also have to look at the fact that this guy has said that they only got hair cells growing in mice and then acknowledges a dB increase was achieved in people as well. Yet interestingly he provided no supporting information to explain why there could have been a dB increase without hair cell regrowth. Furthermore it is interesting that he ignores other facts and achievements from the inaugural trial like the improvement in word scores. Something tells me that this omission was on purpose because acknowledging it would flat out contradict the other criticisms he had made.

In fact it is incredibly interesting that he fails to back up nearly all his negative/dismissive claims about the work of Frequency Therapeutics with any evidence whatsoever. Even when he used evidence to support these negative/critical claims he was making, the evidence used seemed to reject the widely accepted standards.

This article and this doctor's comments lead me to the belief that this was possibly produced to criticise FX-322 and Frequency Therapeutics to serve the interests or purpose of another organisation. One can liken this to those stories on a topic or an issue in magazines and papers which are actually thinly veiled advertisements for a product/service/event being provided by an organisation.

It simply doesn't make sense that a research doc could ignore so many obvious and basic scientific rules and facts when making his statements. I get the feeling this is wilful and also maybe some strange ulterior motive might be coming into play.

 

It was strange.

There were a couple of statements in that article that were blatantly false such as 10 dB being suggested to be within the retest of error and FX-322 not shown to regrow hair cells in adult mammals (which it did in both adult rodents and explant studies).

I honestly think it was the writer looking for doctors willing to say negative statements to appear unbiased but it isn't completely unheard of for there to be "hit pieces" against publicly traded companies. This happened a lot with Sarepta, a biotech I invested in years ago.

 

He’s a pioneering surgeon in cochlear implants. He also appears to have a vested interest in the technology if he still sits on the Scientific Advisory Board for Iotamotion.

https://www.hearingreview.com/heari...announces-formation-scientific-advisory-board

 

And the article itself says Cheng is on the Scientific Advisory Board for Decibel Therapeutics.

 

My own theory is that if you had mild hearing loss, you are less likely to have widespread damage so your 8000 Hz may not be affected but (especially if noise induced which they selected for) you may have a notch or two in lower frequencies.

I really wish we could see the audiograms of the patients, that would be so helpful.

 

This article's absolutely a hit job on FX-322 and also Frequency Therapeutics. I remember our English teacher going through these type of articles and their purpose(s) at school. She said the whole idea of them is to use facts like statistical data and comments from 'experts' to make it look like they've written a believable, legitimate and factual article.

Yet what they actually do is manipulate these facts and comments and 'report' them in a disingenuous way to make the readers form the opinion or conclusion on the topic that the author and/or article's sponsor wants them to form.

We have already alluded to the article's disingenuous and erroneous reporting of stats relating to FX-322 trials. Yet have a look at the doctors who got asked to comment. A cynical individual might actually think that they have deliberately chosen them. ? Interestingly they all work and undertake research in the hearing field and medicine like OTO-413 or FX-322 achieving positive outcomes would probably have an adverse impact on their work/research.

When you take the fabric of the article apart, there are clear indications that the article has been crafted to negatively reflect on FX-322 and surely there has to be an underlying reason for this.

I'm telling you now, I'm feeling that there is going to be a lot of attempts at smearing Frequency Therapeutics in the next few years from from various groups within the hearing sector.

I think that Frequency Therapeutics achievements thus far have demonstrated FX-322 is a legit medicine and therefore it will be a disruptor to the industry as it currently stands. Also their methodology is excellent and actually at this stage seems very hard to criticise.

It seems Frequency Therapeutic's work to date has upset a lot of people who fall in the status quo and they may actually be starting to demonstrate their displeasure and using Frequency Therapeutics as the punching bag because they are at the front and they are the face of this.

 

Thanks. I knew that name had popped up somewhere before. I had an inkling he was working more widely than just being a doctor.

I might be basically seen as a cynic, however I have a pretty good read on things when it seems that someone might have an underlying motive or when things don't seem 100% legit. This doctor's comments definitely fell into both of these categories

 

I'm curious if improvement above 8 kHz is somehow more difficult to achieve than below 8 kHz with FX-322. Granted, I'd be happy to take either at this point, but my concern is above 8 kHz.

 

I'd hold off before turning a difference of opinion into evidence of malice. Anyway, I found this. Agree or not, the guy's statement isn't out of the ballpark.

https://www.bc-legal.co.uk/bc-disea...a-basis-for-nihl-claims-handling-schemes.html.

“The central tool in diagnosis is the audiogram. Audiograms are taken in steps of 5 dB at each frequency. They are variable and not generally exactly repeatable. Where 2 audiograms taken at about the same time vary, the results where there is variation may reasonably be averaged if the difference is not more than 10 dB. Up to 10 dB is therefore an acceptable margin of error”.

 

It is interesting that you point out the "hearing sector". The hearing aid industry throughout the world is huge and has enjoyed for many years as an industry monopoly on providing 'patients' with an answer to getting on with their lives. The Audiologist is the middle man or woman you go to in order to purchase a $6K hearing aid after undergoing an audiogram. Frequency Therapeutics is delivering a lasting, natural solid solution in the advent of FX-322 and, therefore, threatens an industry that has long dominated the 'hearing sector'.

Hearing aids will still be in demand for many with severe-profound hearing loss but the sector will receive a much smaller slice of the pie. The economics of it all, it seems, has stirred up a hornet's nest. I could sense it in the reply from my audiologist when I mentioned FX-322 - "trials have been going on since the mid 90's"

 

Nobody can definitively say because there is no data published as of yet on above 8 kHz.

However there are a number of logical assumptions which can be made based off of the information that we have from both the inaugural trial and also with what we know about how a cochlear functions.

I have tried to logically and sequentially order these:

- The very high frequencies are at the outside of the cochlear (eg: 20000 Hz) and the lower frequencies are furthest in (eg: 250 Hz).

- Based upon the layout of a cochlear, the medicine should hit the very high frequencies first, as they are closer to where the medicine is injected and treat these much more easily than the lower frequencies.

- In the phase1/2 trial, the only dB improvement noted was at 8000 Hz.

This is because the trial's audiogram testing ceiling was 8000 Hz and as a result nothing was tested above this.

- However the word recognition scores also improved in a large number of participants who received FX-322.

Some of these improvements were deemed to be not statistically significant according to the trial reporting criteria, however many felt that they were significant from a practical perspective.

- Based off of the word recognition score improvements, it is assumed a benefit was obtained in the very high frequencies.

This conclusion could be reasonably made because it is seemingly now understood that the very high frequencies (those above 8000 Hz) assist with word and sound clarity.

- Therefore based off of the information obtained from the phase1/2 trial, it is highly likely that there was improvement in the very high frequencies.

We can reasonably assume this fact based on:

> The improvement in word recognition scores across a very high percentage of those given FX-322.

> The fact that the medicine would have had to hit the areas of the cochlear where frequencies from 20000 Hz to 8000 Hz are in order to reaching 8000 Hz which it treated favourably.

Therefore the evidence and information we have about the performance and benefit provided by FX-322 to date indicates that the medicine is highly likely to provide good benefit with the very high frequencies above 8000 Hz. We will need to wait for the official trial data to have definitive evidence either way, however it is looking very promising.

 

Yes, he is a specialist @ Stanford.

I guess it‘s normal that there are always other opinions, especially if the dataset leaves some space for interpretation.

I remember when Marcelo Rivolta published some findings of stem cell treatment for hearing regeneration, it was also criticized by a top researcher of Stanford.

Yet now Rivolta has got funding and established Rinri Therapeutics.

So there is probably some competition between the labs, but it isn‘t necessarily the case. At this stage it‘s rocket science with trial and error with many uncertainties.

I also remember a researcher offering a contrary opinion in regards to the Novartis Atoh1 trial. He told me that nobody else in the field could replicate their results in the lab, so he was very skeptical... same guy is also cautious about FX-322, but he welcomes this step even though he is also involved in other companies who are working on hair cell regeneration.

I just pray that the FX-322 Phase 2a results show us further positive trends and that everything is fast-tracked.

 

Hmm... I can't hear anything above 16 kHz in my right ear. Absolutely zero. But the otoemissions are within the normal range.

Do you think FX-322 can help me?

 

Are we supposed to be able to hear above that frequency? Don't we lose those frequencies due to the normal aging process.

 

During the examination, I was 22 years old. I can hear in my left ear up to 20 kHz. And the tinnitus is mostly in my right ear.

 

Yes, we do lose those frequencies as we get older. Some people lose them faster than others.

Read what tommyd87 wrote in the post above. His reasoning is sound and right on target. At this point we think there is a good chance that 8k frequencies improved and that frequencies above 8k improved as well.

I wonder if some of these guys writing negative comments are shorting the stock.....

I'm still staying cautiously optimistic until the data on the next trials can be obtained. We are making a lot of assumptions that could go either way.

 

What do you guys think of this comment on /r/tinnitusresearch?

"I am an audiologist. 5-10 dB HL difference on an audiogram at one frequency (high or low) in one ear is not significant. When you test hearing all day every day you see it happening often. I would not reprogram a hearing aid based on that difference.... Now, even though 5-10 dB HL is not significant, I would reprogram a hearing aid if there were three or more frequencies that changed by 10dB HL and the patient says their CLEAN hearing aid sounds soft/loud.

I also would not get excited about their word recognition improving from 20% to 40% for one person. Their audiogram did not significantly improve, but their word scores did? There are several reasons for that improvement. For example how the BRAIN (not the cochlea) is processing that sound/word heard. The brain is affected by familiarity with a test, attention, fatigue, mood...

Side note: If the results were actually significant, that would be super exciting, but they would still have a long way to go. My next question would be... is this change temporary? Will they need to get this treatment once every 3, 6, 12 months?"

 

Otoacoustic emissions cover from about 500 Hz to around 8000 Hz (or slightly less). Doesn't tell you much in your case. If your tinnitus is caused by cochlear hair cell loss in the ultra high frequency range, then you might be an ideal candidate.

 

Here is a reference to frequencies - age, we should get not obsessed with UHF at certain ages, I am 46 and 13 kHz is not easy, but I can hear it, and it turns out it is perfectly normal.

 

This is interesting coming from a supposed audiologist and actually also makes me ask some questions about what she bases her comments on/how she can support the claims she is making.

Looking at what she has said, there are some things which simply don't make sense. Someone has also failed to provide evidence for their claims either. These are

> They say word recognition scores improved due to the familiarity of the test

I don't know how you can be familiar with a word recognition test as usually the words are never the same. In fact from what I got told apparently there are hundreds of words for this very reason as it allows them to randomise and change things up.

> They dismissed the improvements in word recognition as not being meaningful.

Sorry but I don't know how you can have results in all patients that are somewhat significant and dismiss them as if there was no improvement and benefit whatsoever. When we see someone go from 6 to 15 or from 25 to 47 it is fairly obvious there was some benefit from this medicine. If your word score was so low to begin with that you struggled to get any then it is quite difficult to see how you can suddenly guess 150% more. Same if you go from being mid level to nearly getting a full score.

Also I have never got told the words that I missed in a word recognition test. If you miss them that's it. This simply doesn't happen.

My view is that this audiologist has simply ignored not only the basic theory but the basic fact that you either don't hear or you hear when making her comments. The basic theory of you hear or don't hear has not only been shown as valid but it is also how Frequency Therapeutics has now been able to validate their information from their clinical trirals.

Thus looking at the information, it is much more probable that there was some benefit from FX-322, otherwise they wouldn't have seen the improvements that they did.

> They say that the 10 dB improvement is insignificant yet also question whether this is a temporary or fixed improvement

Based on what we have seen it is fixed. This actually tells me that this audiologist actually might not have read the information properly or they simply don't know what was achieved.

> No comments were made about hearing above 8000 Hz

I felt that this was the most unusual part of their response. They have seemingly said that 8000 HZ is where hearing stops based off their one frequency improvement comment and the fact that word recognition test improvements are due to being familiar with the test.

I also would have thought that this audiologist would know that there are frequencies higher than 8000 Hz and that for the medicine to actually get to 8000 Hz it would have needed to pass all those other frequencies first too.

I would have thought that someone who knows this stuff would have known that hearing goes past 8000 Hz and also maybe knows what its benefits were.

However, when I look at some of the comments generally from this audiologist, I either think that their views might be simplistic or that they then are simply ignoring the data and facts that Frequency Therapeutics and other independent scientists have shown about FX-322. This includes the plausible and reasonable hypothesis that FX-322 has also benefited the very high frequencies and also the frequencies above 8000 Hz help with sound clarity.

Overall this supposed audiologist makes some points which may have some plausibility to them. However, I think that the biggest thing that I take away from this is that they have actually ignored some basic data and basic evidence in their comments, which doesn't make me feel confident that she has supported her claims.

I particularly note the facts that she has said that they would have had to be familiar with the word test and also that hearing seemingly stops at 8000 Hz in her points. Both of these claims are simply not true and also she has put forward no evidence to support them.

This inevitably tells me that either this audiologist might be ill-informed or may be being disingenuous like others have been about FX-322. Thus I am going to take what they have said with a grain of salt as they are not making me feel confident when they do not correctly support their claims.

 

Looks like a case of "see the forest through the trees". We're not reprogramming hearing aids and we should not be surprised an audiologist at a hearing aid clinic feels 10 dB is not significant. The main concern is if this stuff helps tinnitus.